Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43

作者：Uchida Azusa; Sasaguri Hiroki; Kimura Nobuyuki; Tajiri Mio; Ohkubo Takuya; Ono Fumiko; Sakaue Fumika; Kanai Kazuaki; Hirai Takashi; Sano Tatsuhiko; Shibuya Kazumoto; Kobayashi Masaki; Yamamoto Mariko; Yokota Shigefumi; Kubodera Takayuki; Tomori Masaki; Sakaki Kyohei; Enomoto Mitsuhiro; Hirai Yukihiko; Kumagai Jiro; Yasutomi Yasuhiro; Mochizuki Hideki; Kuwabara Satoshi; Uchihara Toshiki; Mizusawa Hidehiro; Yokota Takanori^*

来源：Brain, 2012, 135: 833-846.

DOI：10.1093/brain/awr348

• TDP-43
• Bunina bodies
• cystatin C
• cynomolgus monkeys
• amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to alpha-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.

• 出版日期2012-3
• 单位河北医科大学